title: Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model.
abstract: BACKGROUND
  Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo.
  
  
  METHODS
  Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling.
  
  
  RESULTS
  Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis.
  
  
  CONCLUSIONS
  Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.
authors.affiliation: Pädiatrie 5, Olgahospital, Bismarckstr. 8, 70176, Stuttgart, Germany, c.blattmann@klinikum-stuttgart.de.
authors.forename: C
authors.initials: C
authors.lastname: Blattmann
authors.forename: M
authors.initials: M
authors.lastname: Thiemann
authors.forename: A
authors.initials: A
authors.lastname: Stenzinger
authors.forename: A
authors.initials: A
authors.lastname: Christmann
authors.forename: E
authors.initials: E
authors.lastname: Roth
authors.forename: V
authors.initials: V
authors.lastname: Ehemann
authors.forename: J
authors.initials: J
authors.lastname: Debus
authors.forename: A E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: W
authors.initials: W
authors.lastname: Weichert
authors.forename: P E
authors.initials: PE
authors.lastname: Huber
authors.forename: S
authors.initials: S
authors.lastname: Oertel
authors.forename: A
authors.initials: A
authors.lastname: Abdollahi
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D004307:Dose-Response Relationship, Radiation; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D011836:Radiation Tolerance / Q000187:drug effects*; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000379:methods; D016896:Treatment Outcome
chemical_list: D056572:Histone Deacetylase Inhibitors